Activity Profile of an FDA-Approved Compound Library against Schistosoma mansoni.
Activity Profile of an FDA-Approved Compound Library against Schistosoma mansoni.
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DOI：
10.1371/journal.pntd.0003962
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发表时间：
2015
影响因子：
3.8
通讯作者：
Keiser J
中科院分区：
文献类型：
--
作者：
Panic G;Vargas M;Scandale I;Keiser J
由于计划扩大大规模药物治疗活动，以打击血吸虫病的形式，对吡喹酮作为唯一可用的治疗方法的依赖的担忧，促使对新型抗血吸虫病化合物的研究。药物再利用可能是一种廉价和有效的来源，新的抗组胺药的铅。1600种FDA批准的化合物首先以10 µM的浓度对曼氏血吸虫童虫进行了测定。从该筛选中鉴定的活性化合物以33.33 µM进入成虫筛选，然后进行命中表征。然后选择具有互补药代动力学和毒性特征的电极导线进行体内研究。在体外筛选确定了121和36个化合物活性对童虫和成虫阶段，分别。此外，在体外表征和比较与现有的药代动力学和毒性数据确定了11个在体内的候选人。多拉菌素（10 mg/kg）和氯法齐明（400 mg/kg）在体内具有活性，虫负荷分别降低60.1%和82.7%。这里介绍的工作扩展了已经批准的化合物的抗溶酶体特性的知识，并强调了基于靶点的方法和表型方法之间以及实验室之间观察到的变化。本研究中确定的两种体内活性药物多拉菌素和氯法齐明可广泛获得，并作为新型药物类别作为进一步研究的起点。对于一种对全球健康具有重大意义的疾病，血吸虫病的治疗工具箱非常小-只有吡喹酮用于治疗所有3种主要形式的疾病。虽然药物发现可能是一个漫长、费力和昂贵的过程，特别是对于资金不足的被忽视的疾病，如血吸虫病，但药物回收（也称为重新定位或重新利用）可以绕过一些开发过程并抵消成本。我们进行了一个药物筛选项目，从一个非常不同的适应症组对曼氏血吸虫的1600 FDA批准的化合物。全部1600种化合物首先在体外针对蠕虫的幼虫阶段进行筛选，其中121种药物被鉴定为有效的。然后在体外对蠕虫的成虫阶段筛选这些命中，其中还发现这些命中中的36个在成虫阶段具有活性。然后将命中化合物的安全性和药代动力学特征与其体外活性进行比较，并选择11种化合物用于小鼠研究。其中，氯法齐明和多拉菌素被认为是中度活性，并提出了新的抗溶酶体支架，可以进行进一步的研究。我们的研究结果与以前的体外和计算机化学基因组学工作的结果以及讨论的一致性和不一致性放在一起。
As plans to expand mass drug treatment campaigns to fight schistosomiasis form, worries about reliance on praziquantel as the sole available treatment motivate the investigation for novel antischistosomal compounds. Drug repurposing might be an inexpensive and effective source of novel antischistosomal leads. 1600 FDA approved compounds were first assayed against Schistosoma mansoni schistosomula at a concentration of 10 µM. Active compounds identified from this screen were advanced to the adult worm screen at 33.33 µM, followed by hit characterization. Leads with complementary pharmacokinetic and toxicity profiles were then selected for in vivo studies. The in vitro screen identified 121 and 36 compounds active against the schistosomula and adult stage, respectively. Further, in vitro characterization and comparison with already available pharmacokinetic and toxicity data identified 11 in vivo candidates. Doramectin (10 mg/kg) and clofazimine (400 mg/kg) were found to be active in vivo with worm burden reductions of 60.1% and 82.7%, respectively. The work presented here expands the knowledge of antischistosomal properties of already approved compounds and underscores variations observed between target-based and phenotypic approaches and among laboratories. The two in vivo-active drugs identified in this study, doramectin and clofazimine are widely available and present as novel drug classes as starting points for further investigation. For a disease of large global health importance, schistosomiasis has a disproportionally small treatment tool box- only praziquantel is used to treat all 3 major forms of the disease. While drug discovery can be a long, laborious and expensive process, especially for an under-funded neglected disease such as schistosomiasis, drug recycling (also termed repositioning or repurposing) can bypass some of the development processes and offset the costs. We conducted a drug screening project of 1600 FDA-approved compounds from a very diverse set of indications against Schistosoma mansoni. The full 1600 compounds were first screened in vitro against the larval stage of the worm, of which 121 drugs were identified as active. These hits were then screened on the adult stages of the worm in vitro where 36 of these hits were also found to be active on the adult stage. The safety and pharmacokinetic profiles of hit compounds were then compared to their in vitro activity and 11 compounds were chosen for studies in mice. Of these, clofazimine and doramectin were found to be moderately active, and present new antischistosomal scaffolds with which further investigations can be pursued. Our findings are placed in context with results obtained from previous in vitro and in silico chemogenomics work and agreements and disagreements discussed.